Tardive dyskinesia in schizophrenia: Gene polymorphisms of muscarinic and adrenergic receptors

Abstract

Introduction: Tardive dyskinesia (TD) occurs in 20-30% of patients receiving long-term antipsychotic treatment [1,2]. A certain role belongs to genetic factors that might be related to sensitivity to development of TD. Inventing methods enabling the personifying of psychopharmacotherapy is principle task of fundamental and translational medicine [3]. A hypothetical model exists implying the involvement of muscarinic receptors in the development of TD. Genetic polymorphisms associated with increased activity of M1 receptors or reduced activity of M2 or M4 receptors may increase the incidence of extrapyramidal symptoms. Regarding adrenergic receptors unique assumptions in the literature imply involvement in the onset of antipsychotic side effects referring to the fact that these receptors may be the targets of a number of atypical antipsychotics. Aim: The objective of the study is to determine the possible role of muscarinic and adrenergic receptors genes in the pathogenesis of tardive dyskinesia in patients with schizophrenia. Methods: This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki 1975, revised in Fortaleza, Brazil, 2013), established for experiments involving humans. In total 449 patients with schizophrenia receiving long-term antipsychotic treatment were included in the study after obtaining written informed consent. The presence or absence of dyskinesia was measured with the abnormal involuntary movement scale (AIMS). Patients were divided into two groups: 121 patients with TD and 328 patients without it. Determination of a set of 22 allelic variants of CHRM1, CHRM2, CHRM4 and 2 polymorphisms of ADRA1A was performed by polymerase chain reaction. Frequency distribution of the study sample was tested in accordance with the Hardy-Weinberg equilibrium. To assess the association of different genotypes with the disorder, odds ratio (OR) were calculated. Results: A significant decrease in frequency was observed of the GG genotype (rs1824024) of gene CHRM2 in patients with TD compared to patients without it (χ2 = 6.161, р = 0.046). We found a significant decrease in the frequency of the TT genotype (rs2061174) (CHRM2) in patients with tardive dyskinesia compared to patients without movement disorders. The frequency of the T allele was significantly higher in patients with TD (χ2 = 6.027, р = 0.04). In addition a significant increase in frequency was found of the AA genotype (rs2036108) of gene ADRA1A in patients with TD as compared with the patients without it (χ2 = 8.055, р = 0.018). Discussion: The GG genotype of rs1824024 (CHRM2) carries a protective effect on TD (OR = 0.4, 95% CI: 0.19 – 0.88; χ2 = 6.03, p = 0.03). And the allele T of rs2061174 has predisposing effects on the development of TD (OR = 1.38, 95% CI: 1.1 – 1.9; χ2 = 3.84, p = 0.04). The similar situation was observed with the AA genotype and the A allele of polymorphism rs2036108 (ADRA1A) (OR1 = 4.11, 95% CI: 1.28 – 13.22; χ2 = 8.05, p = 0.02 and OR2 = 1.5, 95% CI: 1.05 – 2.14; χ2 = 5.06, p = 0.02). Conclusions: This study identified associations between muscarinic and adrenergic receptors and development of tardive dyskinesia. Reduction or increasing of the frequency of some genotypes in patients with TD demonstrated the protective or predisposing effect of these genotypes regarding risk of TD. Disclosure statement: This work is supported by RSF grant # 17-75-10055